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Tumour suppressor TRIM33 targets nuclear ?-catenin degradation.

ABSTRACT: Aberrant activation of ?-catenin in the nucleus has been implicated in a variety of human cancers, but the fate of nuclear ?-catenin is unknown. Here we demonstrate that the tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear ?-catenin protein. TRIM33-mediated ?-catenin is destabilized and is GSK-3? or ?-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear ?-catenin. Moreover, protein kinase C?, which directly phosphorylates ?-catenin at Ser715, is required for the TRIM33-?-catenin interaction. The function of TRIM33 in suppressing tumour cell proliferation and brain tumour development depends on TRIM33-promoted ?-catenin degradation. In human glioblastoma specimens, endogenous TRIM33 levels are inversely correlated with ?-catenin. In summary, our findings identify TRIM33 as a tumour suppressor that can abolish tumour cell proliferation and tumorigenesis by degrading nuclear ?-catenin. This work suggests a new therapeutic strategy against human cancers caused by aberrant activation of ?-catenin.

SUBMITTER: Xue J 

PROVIDER: S-EPMC4315364 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Tumour suppressor TRIM33 targets nuclear β-catenin degradation.

Xue Jianfei J   Chen Yaohui Y   Wu Yamei Y   Wang Zhongyong Z   Zhou Aidong A   Zhang Sicong S   Lin Kangyu K   Aldape Kenneth K   Majumder Sadhan S   Lu Zhimin Z   Huang Suyun S  

Nature communications 20150202

Aberrant activation of β-catenin in the nucleus has been implicated in a variety of human cancers, but the fate of nuclear β-catenin is unknown. Here we demonstrate that the tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear β-catenin protein. TRIM33-mediated β-catenin is destabilized and is GSK-3β or β-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear β-catenin. Moreover, protein kinase Cδ, which directly phosphory  ...[more]

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